The present invention relates to a process for preparing sulfonyl pyridazinone aldose reductase inhibitors. The present invention also relates to novel intermediates used in the process to prepare those aldose reductase inhibitors. Accordingly, the compounds prepared by the process of this invention lower sorbitol levels and, thus, lower fructose levels and have utility in the treatment and/or prevention of diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals.
The enzyme aldose reductase is involved in regulating the reduction of aldoses, such as glucose and galactose, to their corresponding polyols, such as sorbitol and galactitol. Sulfonyl pyridazinone compounds of Formula I of this invention, prodrugs of such compounds and pharmaceutically acceptable salts of such compounds and prodrugs, are useful as aldose reductase inhibitors in the treatment and prevention of diabetic complications of humans and other mammals associated with increased polyol levels in certain tissues (e.g., nerve, kidney, lens and retina tissue) of affected humans and other mammals.
Commonly assigned U.S. Provisional Patent Application No. 60/280,051, which is incorporated herein by reference, discloses compounds of the formula 
wherein A, R1, R2 and R3 are defined as set forth therein.
This invention is directed to a process for preparing a compound of the formula 
wherein R1 and R2 are each independently hydrogen or methyl; and R3, R4, R5 and R6 are each independently H, halo, formyl, (C1-C6)alkyl optionally substituted with up to three fluoro, (C1-C6)alkoxy optionally substituted with up to three fluoro, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl or naphthyl, wherein said benzyl, phenyl and naphthyl are optionally independently with up to two substituents independently selected from halo, (C1-C6)alkyl optionally substituted with up to three fluoro, (C1-C6)alkoxy optionally substituted with up to three fluoro and (C1-C4)alkoxy-(C1-C4)alkyl;
comprising the consecutive steps of:
(a) reacting a compound of the formula 
wherein R3, R4, R5 and R6 are each independently defined as set forth above, with an organolithium compound in the presence of a sulfur source in a first reaction inert solvent to form the reactive intermediate 
(b) reacting said reactive intermediate IIa with a compound of the formula 
to form a compound of the formula 
(c) reacting said compound of the formula IV with an alkaline (C1-C2)alkoxide in a (C1-C2)alkanol to form an ether compound of the formula 
wherein Alk is (C1-C2)alkyl;
(d) reacting said compound of the formula V with a mineral acid to form a compound of the formula 
(e) oxidizing said compound of the formula VI in a second reaction inert solvent to form a compound of the formula I.
In a preferred process of this invention, step (c) and step (d) are performed together in situ. In a further preferred process of this invention, in step (a) said organolithium compound is n-butyllithium, said first reaction inert solvent is tetrahydrofuran and said sulfur source is S8; in step (c) said alkaline (C1-C2)alkoxide is sodium methoxide and said (C1-C2)alkanol is methanol; and in step (d) said compound of formula VI is oxidized with urea-hydrogen peroxide in the presence of trifluoroacetic anhydride and said second reaction inert solvent is tetrahydrofuran.
In a still further preferred process of this invention, R3, R4, R5 and R6 are each independently hydrogen, methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl or phenyl. In a still further preferred process of this invention, R1, R2, R4 and R5 are each hydrogen; R3 is 3-methyl and R6 is 5-chloro.
This invention is also directed to compounds of the formula 
and pharmaceutically acceptable salts thereof, wherein R1 and R2 are each independently hydrogen or methyl; and R3, R4, R5 and R6 are each independently H, halo, formyl, (C1-C6)alkyl optionally substituted with up to three fluoro, (C1-C6)alkoxy optionally substituted with up to three fluoro, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl or naphthyl, wherein said benzyl, phenyl and naphthyl are optionally independently with up to two substituents independently selected from halo, (C1-C6)alkyl optionally substituted with up to three fluoro, (C1-C6)alkoxy optionally substituted with up to three fluoro and (C1-C4)alkoxy-(C1-C4)alkyl.
A preferred group of compounds of formula IV of this invention are those compounds, designated as Group A, and pharmaceutically acceptable salts thereof, wherein R3, R4, R5 and R6 are each independently hydrogen, methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl or phenyl.
A preferred compound of this invention is the compound wherein R1, R2, R4 and R5 are each hydrogen; R3 is 3-methyl and R6 is 5-chloro, having the structure 
This invention is also directed to a process for preparing a compound of the formula IV above wherein R1 and R2 are each independently hydrogen or methyl; R3, R4, R5 and R6 are each independently H, halo, formyl, (C1-C6)alkyl optionally substituted with up to three fluoro, (C1-C6)alkoxy optionally substituted with up to three fluoro, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl or naphthyl, wherein said benzyl, phenyl and naphthyl are optionally independently with up to two substituents independently selected from halo, (C1-C6)alkyl optionally substituted with up to three fluoro, (C1-C6)alkoxy optionally substituted with up to three fluoro and (C1-C4)alkoxy-(C1-C4)alkyl;
comprising the consecutive steps of:
(a) reacting a compound of the formula II wherein R3, R4, R5 and R6 are each independently defined as set forth above with an organolithium compound in the presence of a sulfur source in a reaction inert solvent to form a reactive intermediate of the formula IIa; and
(b) reacting said reactive intermediate IIa with a compound of the formula III to form a compound of the formula IV.
In that process, it is preferred that said organolithium compound is n-butyllithium, said reaction inert solvent is tetrahydrofuran and said sulfur source is S8. It is particularly preferred that R3, R4, R5 and R6 are each independently hydrogen, methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl or phenyl. It is still further preferred that R1, R2, R4 and R4 are each hydrogen; R3 is 3-methyl and R6 is 5-chloro.
This invention is also directed to a process for preparing the compound of the formula 
comprising the consecutive steps of:
(a) reacting the compound of the formula 
with n-butyllithium in the presence of S8 in tetrahydrofuran to form the reactive intermediate 
(b) reacting said reactive intermediate XIIa with the compound of the formula 
to form the compound of the formula 
(c) reacting said compound of the formula XIV with sodium methoxide in methanol to form the compound of the formula 
(d) reacting said compound of the formula XV with concentrated hydrochloric acid to form the compound of the formula 
(e) oxidizing said compound of the formula XVI with hydrogen peroxide-urea complex in the presence of trifluoroacetic anhydride in tetrahydrofuran to form the compound of the formula XI. It is particularly preferred that step (c) and step (d) are performed in situ.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in Formula IV, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36CI, respectively. Compounds of Formula IV of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formula IV of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. The invention also includes processes of this invention whereby isotopically labeled compounds are used therein.
By xe2x80x9chaloxe2x80x9d is meant chloro, bromo, iodo, or fluoro.
By xe2x80x9calkylxe2x80x9d is meant straight or branched chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By xe2x80x9calkoxyxe2x80x9d is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tertiary butoxy. By xe2x80x9calkoxidexe2x80x9d is meant straight chain saturated alkyl or branched saturated alkyl having a negative charge on the oxygen. Exemplary of such alkoxide groups (assuming the designated length encompasses the particular example) are methoxide, ethoxide, propoxide, isopropoxide, butoxide, isobutoxide and tertiary butoxide.
The expression xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to pharmaceutically acceptable acid addition. The expression xe2x80x9cpharmaceutically-acceptable acid addition saltsxe2x80x9d is intended to include, but is not limited to, such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. A particularly preferred salt is the sodium salt.
The pharmaceutically acceptable acid addition salts of the compounds of this invention may be readily prepared by reacting the free base form of said compounds with the appropriate acid. When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent. They can be further purified by crystallization from (C1-C6)alcoholic solvents such as methanol, ethanol or isopropanol or from ketonic solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
As used herein, the expressions xe2x80x9creaction inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refer to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
As used herein, the term xe2x80x9creactive intermediatexe2x80x9d refers to a compound which is formed during the course of a reaction which is not isolated. A reactive intermediate is generally a compound which is not isolatable under ordinary conditions and which is xe2x80x9cquenchedxe2x80x9d by the addition of another reagent which reacts with the reactive portion of the reactive intermediate.
The term xe2x80x9cin situ,xe2x80x9d where used herein, indicates that two steps are carried out in one reaction vessel without isolation of an intermediate compound which could have been isolated if so desired.
Hydrates and solvates of the compounds of this invention are also included.
The chemist of ordinary skill in the art will also recognize that certain compounds of Formula I of this invention can exist in tautomeric form, i.e., that an equilibrium exists between two isomers which are in rapid equilibrium with each other. A common example of tautomerism is keto-enol tautomerism, i.e., 
Examples of compounds which can exist as tautomers include hydroxypyridines, hydroxypyrmidines and hydroxyquinolines. In particular, a person skilled in the art will recognize that the pyridazinones of the instant invention can exist as two separate tautomers, e.g., 
Generally, in this application, the tautomeric forms of such compounds are depicted and named as a pyridazinone. However, the skilled person will recognize that such compounds may also be depicted and/or named as a hydroxypyridazine. Other examples will be recognized by those skilled in the art. All such tautomers and mixtures thereof are included in the compounds that are prepared by the processes of this invention.
Whenever the structure of a cyclic radical is shown with a bond drawn from outside the ring to inside the ring, it will be understood by those of ordinary skill in the art to mean that the bond may be attached to any atom on the ring with an available site for bonding. If the cyclic radical is a bicyclic or tricyclic radical, then the bond may be attached to any atom on any of the rings with an available site for bonding. For example, 
represents any or all of the following radicals: 
Other features and advantages will be apparent from the specification and claims which describe the invention.